Failure of sustained engraftment (resistance) has become the major obstacle to successful use of T-cell depleted marrow transplants. We propose to study both in vitro and in vivo the mechanism of graft resistance in a canine model of marrow transplantation. Early and late graft failures, occurring in histocompatible and histoincompatible transplants, will be examined. Preliminary data implicate host large granular lymphocytes (LGL) as mediating resistance in histoincompatible recipients and T cells as causing resistance in histocompatible dogs. Our main emphasis will be on histoincompatible recipients, in which we will assess whether resistance is due to direct cytotoxicity or rather to production of soluble factors by LGL. We will attempt to abrogate resistance by treatment of incompatible recipient dogs prior to transplantation with monoclonal antibodies specific for canine LGL. In addition, in dogs in which we have abrogated resistance by high dose total body irradiation, we will carry out experiments aimed at restoring resistance by infusion of various subpopulations of host mononuclear cells. The overall goal of this proposal is to determine which host cells mediate marrow graft resistance in order to design effective conditioning regimens that will eliminate these cells prior to marrow transplantation in man. This would enable transplantation across major histocompatibility barriers using T-depleted marrow without risk of eventual marrow graft failure.